Molecular Cancer Therapeutics最新文献_第5页

Farnesyl Transferase Inhibitor KO-2806 (Darlifarnib) Enhances the Antitumor Activity of Tyrosine Kinase Inhibitors in RCC. 法尼基转移酶抑制剂KO-2806 （darlifarnib）增强酪氨酸激酶抑制剂在RCC中的抗肿瘤活性。

IF 6.9 2区医学

Molecular Cancer Therapeutics Pub Date : 2026-09-02 DOI: 10.1158/1535-7163.MCT-25-0449

Jovylyn G Gasendo, Stacia Chan, Hetika V Patel, Alison E Smith, Linda Kessler, Yahu A Liu, Amitava Mitra, Francis Burrows, Shivani Malik

{"title":"Farnesyl Transferase Inhibitor KO-2806 (Darlifarnib) Enhances the Antitumor Activity of Tyrosine Kinase Inhibitors in RCC.","authors":"Jovylyn G Gasendo, Stacia Chan, Hetika V Patel, Alison E Smith, Linda Kessler, Yahu A Liu, Amitava Mitra, Francis Burrows, Shivani Malik","doi":"10.1158/1535-7163.MCT-25-0449","DOIUrl":"10.1158/1535-7163.MCT-25-0449","url":null,"abstract":"Antiangiogenic tyrosine kinase inhibitors (TKI) targeting vascular endothelial growth factor receptor (VEGFR) remain the backbone of therapy in advanced renal cell carcinoma (RCC). However, durability of responses is limited and resistance typically arises. Thus, there is an urgent need for therapeutic agents that enhance responses to TKIs, including in patients who progress on prior TKI therapies. In this study, we show that the farnesyl transferase inhibitor (FTI) KO-2806 inhibits mammalian target of rapamycin complex 1 (mTORC1) signaling in endothelial cells to enhance the antiangiogenic properties of TKIs. This translates to tumor regressions and robust inhibition of tumor neovascularization in preclinical models of RCC exposed to the combination of KO-2806 and anti-VEGFR TKIs. KO-2806 also sensitizes tumors previously progressing on anti-VEGFR TKIs, suggesting potential benefits of KO-2806 as a combination partner across the treatment continuum in RCC.","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"1469-1479"},"PeriodicalIF":6.9,"publicationDate":"2026-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13535317/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147513565","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

A Novel CDK12 Inhibitor Induces Homologous Recombination Deficiency to Enhance PARP Inhibitor Efficacy in Uterine Serous Carcinoma. 一种新的CDK12抑制剂诱导同源重组缺陷增强PARP抑制剂在子宫浆液性癌中的疗效。

IF 6.9 2区医学

Molecular Cancer Therapeutics Pub Date : 2026-09-02 DOI: 10.1158/1535-7163.MCT-25-0954

Shunsuke Kawahara, Mana Taki, Junzo Hamanishi, Shunsuke Ebara, Ryusuke Murakami, Kohei Hamada, Koichi Watanabe, Yuko Hosoe, Yuka Mise, Shiro Takamatsu, Taito Miyamoto, Rin Mizuno, Koji Yamanoi, Ken Yamaguchi, Hiroko Yamakawa, Nobuyuki Kakiuchi, Tsukasa Baba, Seishi Ogawa, Daisuke Morishita, Kosuke Yusa, Masaki Mandai

{"title":"A Novel CDK12 Inhibitor Induces Homologous Recombination Deficiency to Enhance PARP Inhibitor Efficacy in Uterine Serous Carcinoma.","authors":"Shunsuke Kawahara, Mana Taki, Junzo Hamanishi, Shunsuke Ebara, Ryusuke Murakami, Kohei Hamada, Koichi Watanabe, Yuko Hosoe, Yuka Mise, Shiro Takamatsu, Taito Miyamoto, Rin Mizuno, Koji Yamanoi, Ken Yamaguchi, Hiroko Yamakawa, Nobuyuki Kakiuchi, Tsukasa Baba, Seishi Ogawa, Daisuke Morishita, Kosuke Yusa, Masaki Mandai","doi":"10.1158/1535-7163.MCT-25-0954","DOIUrl":"10.1158/1535-7163.MCT-25-0954","url":null,"abstract":"Uterine serous carcinoma (USC) is an aggressive p53-mutated endometrial carcinoma that exhibits gene mutations in homologous recombination (HR) pathways, similar to high-grade serous ovarian carcinoma (HGSOC). However, the therapeutic effect of PARP inhibitors on USC is limited. This study investigated cyclin-dependent kinase 12 (CDK12), a transcriptional regulator of HR genes, and evaluated the efficacy of a novel CDK12 inhibitor, CTX-439, combined with a PARP inhibitor, olaparib, in patient-derived xenograft (PDX) models of USC. We evaluated the HR deficiency (HRD) scores, genetic alterations, and HR-related gene abnormalities, including CDK12, in USC, other histopathologic types of uterine endometrial carcinoma, and HGSOC using The Cancer Genome Atlas dataset. We also assessed CDK12 function and CTX-439 efficacy in USC utilizing USC cell lines and PDX models. USC exhibited a higher HRD score than other histologic subtypes of uterine endometrial carcinoma but lower than HGSOC. CDK12 amplification occurred more frequently in USC than in HGSOC but was not associated with HRD scores. Tumors with CDK12 amplification demonstrated high CDK12 expression, which correlated with poor prognosis in USC. The CDK12 inhibitor CTX-439 suppressed HR-related gene expression, including BRCA1 and BRCA2; induced apoptosis and DNA damage; and inhibited tumor growth in USC PDX models with high CDK12 expression. Furthermore, CDK12 inhibition enhanced tumor sensitivity to the PARP inhibitor olaparib in USC PDX models. This study indicates that CDK12 is a potential therapeutic target for enhancing the antitumor effects of PARP inhibitors in patients with USC.","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"1455-1468"},"PeriodicalIF":6.9,"publicationDate":"2026-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147434305","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

CDK2 Inhibition and Eradication of Aneuploid Cancers: Promise Meets Resistance. CDK2抑制和根除非整倍体癌症：希望遇到阻力。

IF 6.9 2区医学

Molecular Cancer Therapeutics Pub Date : 2026-09-02 DOI: 10.1158/1535-7163.MCT-26-0181

Samuel C Okpechi, Zibo Chen, Liliya Tyutyunyk-Massey, Yair Alfaro, Xi Liu, Ethan Dmitrovsky

{"title":"CDK2 Inhibition and Eradication of Aneuploid Cancers: Promise Meets Resistance.","authors":"Samuel C Okpechi, Zibo Chen, Liliya Tyutyunyk-Massey, Yair Alfaro, Xi Liu, Ethan Dmitrovsky","doi":"10.1158/1535-7163.MCT-26-0181","DOIUrl":"10.1158/1535-7163.MCT-26-0181","url":null,"abstract":"Aneuploidy is a cancer hallmark that causes resistance to anticancer drugs and promotes aggressive tumors. Thus, aneuploidy is a consequential feature of human malignancy. This review addresses how cyclin-dependent kinase 2 (CDK2) inhibition targets a broad array of aneuploid cancers for proapoptotic death by engaging a death program called anaphase catastrophe. This program eliminates aneuploid cancers while sparing non-aneuploid epithelial cells, thereby providing a favorable therapeutic window. Despite CDK2 inhibition, a residual population of polyploid cancer cells persists in both in vitro and in vivo settings. This polyploid cancer cell population is resistant to apoptosis conferred by CDK2 inhibition of aneuploid cancers. This provides a basis for clinical drug resistance. The triggering apoptotic death of aneuploid cancers via CDK2 antagonism is compromised by the presence of this apoptosis-resistant population. To elucidate the nature of this polyploid population, these apoptotic-resistant cells were isolated and were found enriched for expressed cyclin-dependent kinase 1 (CDK1) and kinesin superfamily proteins (KIFs). Intriguingly, combining CDK2 inhibition with antagonists for CDK1 or KIF species markedly promoted anticancer effects in aneuploid cancers. This clinically-tractable combined regimen is hypothesized to expose aneuploid cancers to eradication after CDK2 antagonism. Future clinical trials should explore this possibility.","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"1447-1454"},"PeriodicalIF":6.9,"publicationDate":"2026-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147840480","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Amanitin-Based Fc-Small Molecule-Drug Conjugates with Noncleavable Linker: A Novel Therapeutic Strategy for Prostate Cancer Targeted Therapy. 基于amanita的fc -小分子药物与不可切割连接体的结合：前列腺癌靶向治疗的新策略。

IF 6.9 2区医学

Molecular Cancer Therapeutics Pub Date : 2026-09-02 DOI: 10.1158/1535-7163.MCT-25-1274

Daniela Carraturo, Francesca Gallo, Marisa Schmitt, Kristin Decker, Christian Orlik, Andreas M Pahl, Torsten Hechler

{"title":"Amanitin-Based Fc-Small Molecule-Drug Conjugates with Noncleavable Linker: A Novel Therapeutic Strategy for Prostate Cancer Targeted Therapy.","authors":"Daniela Carraturo, Francesca Gallo, Marisa Schmitt, Kristin Decker, Christian Orlik, Andreas M Pahl, Torsten Hechler","doi":"10.1158/1535-7163.MCT-25-1274","DOIUrl":"10.1158/1535-7163.MCT-25-1274","url":null,"abstract":"Prostate cancer remains a major global health burden, with limited options and poor prognosis in advanced stages. To extend survival and improve the quality of life for patients, targeted therapies have become an emerging treatment modality. Antibody-drug conjugates (ADC) have shown huge clinical success but only limited therapeutic effects in prostate cancer as their large size limits tumor penetration. Small molecule-drug conjugates (SMDC), consisting of a small molecule as a binding moiety and a cytotoxic drug, offer advantages due to their smaller size, but their short plasma half-life and poor efficacy have hampered their clinical breakthrough so far. Fragment crystallizable (Fc)-grafted SMDCs (Fc-SMDC) combine a SMDC with the half-life-extending Fc fragment of an antibody. So far, the Fc fragments have been attached directly to the small molecule-drug complex, making an enzymatic cleavable linker for payload release an indispensable prerequisite. We report a first-in-class Fc-SMDC targeting PSMA and carrying α-amanitin with a noncleavable linker. The payload is conjugated directly to the Fc region via an engineered cysteine to separate it from the targeting moiety. This approach enables, in contrast to conventional Fc-SMDCs, the use of noncleavable linkers for minimal premature drug release, increased plasma stability, and low systemic toxicity. Due to the noncleavable linker, our conjugate showed high tolerability and an extended half-life, resulting in prolonged tumor exposure and excellent antitumor efficacy in xenograft models. Together with the favorable tolerability in non-human primates, these findings highlight the potential for a next-generation treatment for prostate cancer.","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"1433-1446"},"PeriodicalIF":6.9,"publicationDate":"2026-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13535313/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147499362","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

M6 Metabolite Contributes to the Efficacy of the Rac/Cdc42 Inhibitor MBQ-167 in Metastatic Breast Cancer. M6代谢物有助于Rac/Cdc42抑制剂MBQ-167治疗转移性乳腺癌的疗效。

IF 6.9 2区医学

Molecular Cancer Therapeutics Pub Date : 2026-09-02 DOI: 10.1158/1535-7163.MCT-25-1319

Nilmary Grafals-Ruiz, Julia I Medina, Jessica Colón Gonzalez, Anamaris Torres-Sanchez, Karla M Martin-Ortiz, Cornelis P Vlaar, Jorge Duconge, José Rodríguez-Orengo, Suranganie Dharmawardhane

{"title":"M6 Metabolite Contributes to the Efficacy of the Rac/Cdc42 Inhibitor MBQ-167 in Metastatic Breast Cancer.","authors":"Nilmary Grafals-Ruiz, Julia I Medina, Jessica Colón Gonzalez, Anamaris Torres-Sanchez, Karla M Martin-Ortiz, Cornelis P Vlaar, Jorge Duconge, José Rodríguez-Orengo, Suranganie Dharmawardhane","doi":"10.1158/1535-7163.MCT-25-1319","DOIUrl":"10.1158/1535-7163.MCT-25-1319","url":null,"abstract":"Metastasis remains a major challenge in cancer treatment because of the lack of effective targeted therapies. MBQ-167, a first-in-class dual Rac/Cdc42 inhibitor currently in a phase I clinical trial, has demonstrated promising activity in preclinical breast cancer models by reducing tumor burden and preventing metastasis. To characterize its metabolism, we conducted liver microsome assays and identified several MBQ-167 metabolites. Of these, M6 was the primary metabolite from dog and human plasma following oral administration of MBQ-167. The M6cpharmacokinetics profile parallels that of MBQ-167 in human plasma from patients with advanced breast cancer enrolled in the clinical trial. In metastatic breast cancer cell lines (HER2-BM, MDA-MB-231, and MDA-MB-468), M6 exhibited minimal effects on cell viability and apoptosis but strongly inhibited Rac1 activation without affecting Cdc42 activation. M6 also inhibited phosphorylation of group 1 p21-activated kinases (PAK) more effectively than MBQ-167 and significantly reduced breast cancer cell migration in wound healing and Transwell assays. In vivo studies with immunocompromised mice bearing HER2-BM tumors demonstrated that M6 inhibits tumor growth and metastasis to the lungs, livers, and kidneys by ∼90%, comparable with MBQ-167. These findings suggest that M6 exhibits potent anticancer properties both in vitro and in vivo, potentially contributing to the sustained efficacy of MBQ-167 in metastatic breast cancer.","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"1480-1490"},"PeriodicalIF":6.9,"publicationDate":"2026-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13071895/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147355898","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

DHX9 Inhibition Enhances Paclitaxel Sensitivity by Inducing Mitotic Failure in Ovarian and Endometrial Cancers. DHX9抑制通过诱导卵巢癌和子宫内膜癌有丝分裂失败增强紫杉醇敏感性。

IF 6.9 2区医学

Molecular Cancer Therapeutics Pub Date : 2026-09-02 DOI: 10.1158/1535-7163.MCT-25-1196

Tzu-Ting Huang, Jayakumar R Nair, Courtney Bowen, Jennifer Castro, Darryl Nousome, Sunaina Nayak, Serena J Silver, Jung-Min Lee

{"title":"DHX9 Inhibition Enhances Paclitaxel Sensitivity by Inducing Mitotic Failure in Ovarian and Endometrial Cancers.","authors":"Tzu-Ting Huang, Jayakumar R Nair, Courtney Bowen, Jennifer Castro, Darryl Nousome, Sunaina Nayak, Serena J Silver, Jung-Min Lee","doi":"10.1158/1535-7163.MCT-25-1196","DOIUrl":"10.1158/1535-7163.MCT-25-1196","url":null,"abstract":"Recurrent high-grade serous ovarian carcinoma (HGSOC) and endometrial cancer remain major clinical challenges with limited effective treatment options. DExH-box helicase 9 (DHX9), a DNA/RNA helicase essential for genomic stability, has not yet been explored as a therapeutic target in gynecologic cancers. In this study, we show that a selective DHX9 inhibitor (DHX9i) suppresses proliferation in a subset of HGSOC and endometrial cancer cell lines by inducing DNA damage, chromosomal instability, and mitotic failure. This effect was independent of microsatellite instability status and prior resistance to platinum or PARP inhibitors. Genomic analysis indicated that DHX9i resistance was unlikely to be driven by single-gene mutations but was instead associated with copy-number alterations in mitotic spindle and microtubule-regulating genes in both HGSOC and endometrial cancer. Transcriptomic profiling further revealed consistent alterations in microtubule- and spindle-associated pathways in DHX9i-resistant models following DHX9i treatment. Mechanistically, DHX9i induced mitotic defects in DHX9i-sensitive models, whereas resistant lines maintained mitotic integrity. Given the convergence of resistance-associated features on microtubule-related pathways, we combined DHX9i with the microtubule-stabilizing agent paclitaxel to enhance mitotic stress. This combination triggered mitotic disruption and enhanced cytotoxicity in DHX9i-resistant cells. In vivo, the combination led to sustained tumor regression and prolonged survival in both DHX9i-sensitive and DHX9i-resistant models without notable toxicity. Overall, our findings define genomic, transcriptomic, and phenotypic characteristics associated with differential responses to DHX9i and support the clinical evaluation of the DHX9i-paclitaxel combination as a therapeutic strategy in recurrent gynecologic cancers.","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"1501-1512"},"PeriodicalIF":6.9,"publicationDate":"2026-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13098759/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147504243","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Suppressing phosphatidylserine externalization overcomes cancer immune evasion and enhances immunotherapy. 抑制磷脂酰丝氨酸外化克服癌症免疫逃避，增强免疫治疗。

IF 6.9 2区医学

Molecular Cancer Therapeutics Pub Date : 2026-09-02 DOI: 10.1158/1535-7163.MCT-26-0108

Johann S Bergholz, Grace Trombley, Gwendolyn Cusing, Zhaoqi Li, Margaret E Torrence, Geneva J Sganga, Jennifer G Casey, Shangtao Liu, Ashley H Choi, Samuel R Meier, Tenzing Khendu, Yi Yu, Teng Teng, Binzhang Shen, Hannah Stowe, Salam Shaaban, Jannik N Andersen, Serge Gueroussov

{"title":"Suppressing phosphatidylserine externalization overcomes cancer immune evasion and enhances immunotherapy.","authors":"Johann S Bergholz, Grace Trombley, Gwendolyn Cusing, Zhaoqi Li, Margaret E Torrence, Geneva J Sganga, Jennifer G Casey, Shangtao Liu, Ashley H Choi, Samuel R Meier, Tenzing Khendu, Yi Yu, Teng Teng, Binzhang Shen, Hannah Stowe, Salam Shaaban, Jannik N Andersen, Serge Gueroussov","doi":"10.1158/1535-7163.MCT-26-0108","DOIUrl":"https://doi.org/10.1158/1535-7163.MCT-26-0108","url":null,"abstract":"Immune checkpoint blockade (ICB) has transformed cancer therapy, yet many tumors remain refractory to treatment due to diverse immune evasion mechanisms. To uncover novel drivers of ICB resistance, we performed an in vivo CRISPR-Cas9 screen in mice with increasing levels of immune pressure. This screen identified phosphatidylserine (PS) externalization as a potent mediator of immune escape. Tumors with elevated surface PS exposure prevented reinvigoration of CD8+ T cells upon PD-1 blockade, which was associated with increased recruitment of immunosuppressive myeloid cells. Targeting of PS Synthase 1 (PTDSS1) or either of the scramblases, XKR8 or ANO6, sensitized tumors to ICB in vivo. These findings demonstrate that elevated PS exposure constitutes a mechanism of resistance to ICB, and that targeting regulators of PS externalization represents a promising strategy to enhance the efficacy of immunotherapy in refractory tumors.","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2026-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148881221","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Structural basis and preclinical efficacy of MG1124, a novel CEACAM1-targeting antibody synergizing with PD-1 blockade. 与PD-1阻断剂协同作用的新型ceacam1靶向抗体MG1124的结构基础和临床前疗效

IF 6.9 2区医学

Molecular Cancer Therapeutics Pub Date : 2026-08-27 DOI: 10.1158/1535-7163.MCT-26-0454

Jae-Chul Lee, Miyoung Oh, Hye-Mi Nam, Hyun-Jung Cho, Jae Hwan Kim, Byoung Chul Cho, Seonghoon Kim, Byung-Ha Oh, Chang-Woo Lee

{"title":"Structural basis and preclinical efficacy of MG1124, a novel CEACAM1-targeting antibody synergizing with PD-1 blockade.","authors":"Jae-Chul Lee, Miyoung Oh, Hye-Mi Nam, Hyun-Jung Cho, Jae Hwan Kim, Byoung Chul Cho, Seonghoon Kim, Byung-Ha Oh, Chang-Woo Lee","doi":"10.1158/1535-7163.MCT-26-0454","DOIUrl":"https://doi.org/10.1158/1535-7163.MCT-26-0454","url":null,"abstract":"CEACAM1 homodimerization mediates tumor immune evasion, presenting a compelling target to overcome resistance to PD-1 blockade. However, defining a precise structural and pharmacological blueprint for CEACAM1 targeting has remained challenging. Here, we report the discovery and comprehensive preclinical characterization of MG1124, a highly specific, fully human monoclonal antibody targeting the CEACAM1 IgV domain. X-ray crystallographic analysis at a 1.8 Å resolution revealed that MG1124 binds the homodimerization interface with robust affinity (KD = 37.8 nM), physically disrupting both homophilic and heterophilic inhibitory interactions without cross-reacting with highly homologous CEACAM members. This targeted structural blockade effectively reversed CEACAM1-mediated suppression of T-cell receptor signaling, restoring ZAP70 phosphorylation and IL-2 production, while potently enhancing NK- and CD8⁺ T-cell cytotoxicity against CEACAM1-high tumor cells. In vivo, MG1124 reprogrammed the tumor immune microenvironment by increasing effector cytokine production in human CEACAM1 knock-in mice. It also demonstrated robust tumor growth inhibition in humanized non-small cell lung cancer (NSCLC) patient-derived xenograft (PDX) models, synergizing profoundly with PD-1 blockade. Furthermore, multiplex immunofluorescence profiling of human NSCLC tissues confirmed robust CEACAM1 expression across tumor and immune compartments, reinforcing its translational validity. Finally, MG1124 exhibited a highly favorable, drug-like pharmacokinetic profile in cynomolgus monkeys, characterized by prolonged systemic exposure and low clearance. By defining the structural basis of CEACAM1 blockade and demonstrating translational efficacy, this study introduces MG1124 as a novel therapeutic antibody, providing a robust pharmacological foundation for cancer immunotherapy.","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2026-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148840812","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Potent antitumor efficacy of datopotamab deruxtecan compared with sacituzumab govitecan in an intracranial tumor model of triple-negative breast cancer. 在三阴性乳腺癌颅内肿瘤模型中，datopotamab deruxtecan与sacituzumab govitecan的有效抗肿瘤疗效比较

IF 6.9 2区医学

Molecular Cancer Therapeutics Pub Date : 2026-08-26 DOI: 10.1158/1535-7163.MCT-25-1188

Chikako Funasaka, Hiroki Takashima, Daisuke Okajima, Takanori Maejima, Satoru Yasuda, Tsuyoshi Karibe, Shuichi Mitsunaga, Toru Mukohara, Toshihiko Doi, Masahiro Yasunaga

{"title":"Potent antitumor efficacy of datopotamab deruxtecan compared with sacituzumab govitecan in an intracranial tumor model of triple-negative breast cancer.","authors":"Chikako Funasaka, Hiroki Takashima, Daisuke Okajima, Takanori Maejima, Satoru Yasuda, Tsuyoshi Karibe, Shuichi Mitsunaga, Toru Mukohara, Toshihiko Doi, Masahiro Yasunaga","doi":"10.1158/1535-7163.MCT-25-1188","DOIUrl":"https://doi.org/10.1158/1535-7163.MCT-25-1188","url":null,"abstract":"Metastatic brain tumors are common in patients with triple-negative breast cancer (TNBC) and often lead to a poor prognosis. Trophoblast cell surface antigen 2 (TROP2) is overexpressed in TNBC cells and an attractive target molecule in breast cancer. Datopotamab deruxtecan (Dato-DXd) is an antibody-drug conjugate targeting TROP2 that selectively releases payloads in tumors. We evaluated the efficacy and tumor concentration of payload of Dato-DXd and sacituzumab govitecan (SG), another TROP2-directed antibody-drug conjugate, in an intracranial TNBC xenograft model. We established the intracranial tumor model by orthotopically transplanting luciferase-expressing TROP2-positive TNBC cells into the brains of nude mice. Dato-DXd intravenously administered at 10 mg/kg on day 1 significantly reduced tumor size compared with SG administered at 10 mg/kg (average -99.5% vs. -1.8%, p = 0.02). The median survival was 18 days (95% confidence interval [CI]: 14 to not assessed [NA] days) in the control group, 48 days (15 to NA days) in the SG group, and 83 days (49 to NA days) in the Dato-DXd group. The payload released from Dato-DXd was rarely detected in the plasma (DXd: 0.09 ng/mL at maximum [at 6h postdose]), while the released payload of SG in the plasma was much higher than Dato-DXd and gradually decreased (SN-38: 10.8 ng/mL at maximum [at 0h postdose]). Dato-DXd showed greater antitumor activity in the intracranial TNBC model with higher payload accumulation in tumors compared with SG. Further clinical evaluation of Dato-DXd in patients with brain metastasis from TNBC is warranted.","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2026-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148840859","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Anti-4CB1: A Novel Selective HVEM-Blocking Antibody Enhancing T-Cell and Macrophage Immunity Against Solid Tumors. 抗4cb1：一种增强t细胞和巨噬细胞对实体瘤免疫的新型选择性hvem阻断抗体

IF 6.9 2区医学

Molecular Cancer Therapeutics Pub Date : 2026-08-19 DOI: 10.1158/1535-7163.MCT-25-1420

Gilli Galore-Haskel, Efrat Merhavi-Shoham, Mika Shapiro, Roni Bareli, Naama Dror, Sivan Seliktar-Ofir, Katerina Shamalov, Dorit Landstein, Adva Levy-Barda, Goni Hout-Siloni, Jacob Schachter, Eran Sadot, Ram Eitan, Iris Barshack, Shay Golan, Yael Feferman, Effi Yeoshoua, Saeb Eyadat, Eyal Greenberg, Gal Markel

{"title":"Anti-4CB1: A Novel Selective HVEM-Blocking Antibody Enhancing T-Cell and Macrophage Immunity Against Solid Tumors.","authors":"Gilli Galore-Haskel, Efrat Merhavi-Shoham, Mika Shapiro, Roni Bareli, Naama Dror, Sivan Seliktar-Ofir, Katerina Shamalov, Dorit Landstein, Adva Levy-Barda, Goni Hout-Siloni, Jacob Schachter, Eran Sadot, Ram Eitan, Iris Barshack, Shay Golan, Yael Feferman, Effi Yeoshoua, Saeb Eyadat, Eyal Greenberg, Gal Markel","doi":"10.1158/1535-7163.MCT-25-1420","DOIUrl":"https://doi.org/10.1158/1535-7163.MCT-25-1420","url":null,"abstract":"Immune checkpoint inhibitors (ICIs) have improved cancer outcomes; however, many patients fail to respond, highlighting the need for novel targets. HVEM (Herpes Virus Entry Mediator) is an immune regulator with both inhibitory and stimulatory functions, making it a promising therapeutic candidate. We have developed Anti-4CB1, a fully human monoclonal antibody (mAb) that selectively blocks HVEM interactions with BTLA and CD160. Its activity was evaluated in-vitro using human tumor-infiltrating lymphocytes (TILs), peripheral blood mononuclear cells (PBMCs), and M1 macrophages, as well as in ex-vivo patient-derived tumor samples and in-vivo transgenic and humanized mouse models. HVEM expression was also assessed in serum and tumor tissues. Anti-4CB1 enhanced T-cell activation and cytotoxicity, evidenced by increased tumor cell killing, upregulation of activation markers (41BB, CD107a), and elevated IFNγ and TNFα secretion. It also promoted macrophage-mediated phagocytosis. In ex-vivo analyses of 49 patient-derived tumor samples, Anti-4CB1 increased cytotoxicity in 28.5% of cases, including samples unresponsive to anti-PD1. In-vivo, Anti-4CB1 demonstrated significant anti-tumor activity as monotherapy and showed enhanced efficacy in combination with anti-PD1. Additionally, higher tumor HVEM expression correlated with improved response to checkpoint blockade, while elevated soluble HVEM levels were associated with reduced responsiveness to Anti-HVEM. Anti-4CB1 enhances both adaptive and innate anti-tumor immunity and shows activity in anti-PD1 resistant settings. These findings support its potential as a novel therapeutic agent and suggest HVEM as a predictive biomarker for immunotherapy response.","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2026-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148795571","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

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